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Directed Therapy to Combat Mycobacterial Infections*

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Directed Therapy to Combat Mycobacterial Infections* Received: 18 December 2020 | Accepted: 27 December 2020 DOI: 10.1111/imr.12951 INVITED REVIEW Host- directed therapy to combat mycobacterial infections* Gül Kilinç | Anno Saris | Tom H. M. Ottenhoff | Mariëlle C. Haks Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Abstract Netherlands Upon infection, mycobacteria, such as Mycobacterium tuberculosis (Mtb) and nontu- Correspondence berculous mycobacteria (NTM), are recognized by host innate immune cells, triggering Mariëlle C. Haks, Department of a series of intracellular processes that promote mycobacterial killing. Mycobacteria, Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, ZA Leiden however, have developed multiple counter- strategies to persist and survive inside host 2333, The Netherlands. cells. By manipulating host effector mechanisms, including phagosome maturation, email: [email protected] vacuolar escape, autophagy, antigen presentation, and metabolic pathways, patho- Funding information genic mycobacteria are able to establish long- lasting infection. Counteracting these Netherlands Organisation for Scientific Research (NWO- TTW), Grant/Award mycobacteria- induced host modifying mechanisms can be accomplished by host- Number: 16444; European Union (Horizon directed therapeutic (HDT) strategies. HDTs offer several major advantages compared 2020 programme), Grant/Award Number: 847762; IMI2 JU (AMR Accelerator to conventional antibiotics: (a) HDTs can be effective against both drug- resistant and program), Grant/Award Number: 853932 drug- susceptible bacteria, as well as potentially dormant mycobacteria; (b) HDTs are and 853903 less likely to induce bacterial drug resistance; and (c) HDTs could synergize with, or shorten antibiotic treatment by targeting different pathways. In this review, we will explore host- pathogen interactions that have been identified for Mtb for which poten- tial HDTs impacting both innate and adaptive immunity are available, and outline those worthy of future research. We will also discuss possibilities to target NTM infection by HDT, although current knowledge regarding host- pathogen interactions for NTM is limited compared to Mtb. Finally, we speculate that combinatorial HDT strategies can potentially synergize to achieve optimal mycobacterial host immune control. KEYWORDS drug resistance, host- directed therapy, Mycobacterium avium, Mycobacterium tuberculosis, nontuberculous mycobacteria 1 | INTRODUCTION of deaths globally.1 Approximately a quarter of the world's popula- tion is infected with Mtb and in most cases, progression toward TB Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), re- disease is prevented by an efficient host immune response, often mains a major health problem. With an estimated 10 million disease resulting in a latent TB infection (LTBI).1 Five to fifteen percent of cases and 1.4 million deaths in 2019, Mtb is the deadliest infec- LTBI individuals will develop TB disease during their life- time, often tious agent worldwide and TB is one of the top- 10 leading causes concomitant with host immunocompromising conditions, including This article is part of a series of reviews covering Immunity to Mycobacteria appearing in HIV infection and use of immunosuppressive medication. Treatment Volume 301 of Immunological Reviews. of patients with active TB has largely remained unchanged for over Kilinç, Saris, Ottenhoff, and Haks authors are Contributed equally. 30 years,1 and due to its lengthiness (6- 24 months) and considerable This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2021 The Authors. Immunological Reviews published by John Wiley & Sons Ltd. Immunological Reviews. 2021;00:1–22. wileyonlinelibrary.com/journal/imr | 1 2 | KILINÇ et aL side effects, treatment- adherence is low fueling development of regimens, thereby increasing compliance. Fifth, HDT may permit multi- drug and extensive- drug resistance (MDR and XDR). The large dose lowering of standard antibiotics, thus reducing toxicity with- TB disease burden and the increasing incidence of drug resistance out impacting efficacy. Finally, as HDT and mycobacterium- targeting make alternative treatment solutions imperative. compounds (ie, antibiotics) by definition act on different pathways, While the number of TB cases is slowly declining, a trend that combinatorial regimens would be expected to synergize. In this re- may well be broken as a result of the COVID- 19 pandemic,2 the prev- view, we will provide a comprehensive overview of host- pathogen alence of infections known to be caused by nontuberculous myco- interactions that have been identified in Mtb infections and that are bacteria (NTM) is increasing at an alarming rate, currently reaching amenable to targeting by HDTs (summarized in Figure 1 and Table 1). 0.2- 9.8 per 100.000 individuals.3 NTM represent a group of op- Furthermore, despite a limited number of reports, we will also dis- portunistic mycobacterial pathogens that mostly cause pulmonary cuss NTM- mediated host modulation and speculate whether HDTs diseases (PD), predominantly in vulnerable populations due to immu- could also be of interest to combat these mycobacterial infections. nodeficiencies and/or pre- existing lung conditions. Mycobacterium Finally, we will discuss the possibility of combinatorial HDTs that tar- avium (Mav) complex (MAC) and Mycobacterium abscessus (Mab) ac- get distinct host signaling pathways to promote possible synergistic count for the large majority of reported cases.3 Despite extended treatment effects. treatment regimens, clinical outcome is poor, with cure rates of approximately 50%- 88% among MAC- PD patients and 25%- 58% among Mab- infected individuals,3 urging the development of novel 2 | HDT MODULATING INNATE IMMUNE treatment modalities. CELL FUNCTION Mycobacteria are well known for their capability to manipulate intracellular signaling pathways to escape from host- defense mech- 2.1 | Phagocytosis and phagosome maturation anisms in human cells. Mtb is best studied in this regard, but NTM have also been shown to modulate host immune responses, includ- The first potential target for HDT to interfere with host- pathogen in- ing preventing phagosome acidification and maturation or escap- teractions is to modulate mycobacterial host- cell entry. Mycobacteria ing from phagosomes into the nutrient- rich cytosol. Counteracting infect host cells, predominantly alveolar macrophages and epithe- pathogen- induced immune modulation by host- directed therapy lial cells, in the lower respiratory tract, following inhalation of small (HDT) is a promising adjunct therapy to antibiotic therapy to combat bacteria- containing aerosols. Mycobacteria express pathogen- intracellular mycobacterial infections, with several major advantages associated molecular patterns (PAMPs) that are recognized by pat- over current antibiotics. First, HDT can also be effective against tern recognition receptors (PRRs), such as Toll- like receptors (TLRs), MDR/XDR mycobacteria that are insensitive to current standard C- type lectin receptors, and other scavenger receptors expressed on antibiotics. Second, because there is no direct selection pressure on the surface of host cells to initiate phagocytosis.4 especially TLR2, mycobacteria, host- targeting compounds are less likely to result in which forms heterodimers with TLR1 and TLR6 to recognize lipo- drug resistance. Third, host- targeting compounds have the potential proteins or lipopeptides (eg, lipomannan), and TLR4, which recog- to target metabolically inactive, non- replicating bacilli during LTBI, nizes cell wall lipids, glycoproteins, and secreted proteins, are known which are tolerant or resistant to conventional therapies. Fourth, to mediate Mtb- induced cellular activation.5 Mice lacking TLR2 are HDT may allow shortening of current lengthy TB/NTM- treatment more susceptible to infections with virulent Mtb and Mav strains.6- 8 FIGURE 1 Host- pathogen interactions and potential host- directed therapies (HDT). Granulomas are characteristic for tuberculosis and mycobacterial infections in general. Pathologic granulomas are poorly vascularized due to ineffective angiogenesis, leading to hypoxia and concomitant host- cell necrosis and bacterial dissemination. Blocking angiogenesis, preventing host- cell necrosis (or stimulating apoptosis) or inhibiting extracellular matrix (eCM) degradation improves granuloma structure and concomitant disease outcome. Macrophages, key cells in the anti- mycobacterial response, initiate phagocytosis after toll- like receptor (TLR) recognition, which is prevented and/or modulated by mycobacteria. Promoting TLR4 engagement, TLR2 signaling and post- phagocytic signaling via receptor tyrosine kinase are all potential targets for HDT to improve host immunity during mycobacterial infection. After internalization, mycobacteria are located to phagosomes that slowly mature and ultimately fuse with lysosomes, which are all inhibited by mycobacteria. Alternatively, mycobacteria escape to the cytosol where they can be recognized by cytoplasmic pathogen recognition receptor (PRR) and “recaptured” using autophagy, which again is inhibited by mycobacteria. HDTs that (1) prevent phagosomal escape, (2) alleviate blockage of (auto- )phagosome maturation, (3) promote autophagy
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